These baseline levels will be quantitatively summarized and graphically explored, in particular in terms of how they relate to clinical outcomes of interest. Analyses exploring differences in these angiogenic and correlative markers in relation to clinical outcomes will be largely hypothesis-generating. With limited numbers of patients patterns of difference will primarily be looked for using graphical analyses; these can include plots of these marker levels in relation to clinical outcomes to identify potential patterns of interest.

These baseline levels will be quantitatively summarized and graphically explored, in particular in terms of how they relate to clinical outcomes of interest. Analyses exploring differences in these angiogenic and correlative markers in relation to clinical outcomes will be largely hypothesis-generating. With limited numbers of patients patterns of difference will primarily be looked for using graphical analyses; these can include plots of these marker levels in relation to clinical outcomes to identify potential patterns of interest.

Incidence of severe (grade 3+) adverse events, graded according to the National Cancer Institute CTCAE v4.0 [ Time Frame: Up to 1 year ]

The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns. Tolerability of the regimens will be assessed through assessing the number of patients who required dose modifications and/or dose delays. In addition, the proportion of patients who go off treatment due to adverse reactions or even those who refuse further treatment for lesser toxicities that inhibit their willingness to continue participation on the trial will be captured.

Overall survival [ Time Frame: Time from start of treatment to time of death, assessed up to 1 year ]

Side-by-side boxplots will be used to assess possible differences in this change between responders and non-responders, and scatterplots can assess the influence of baseline thyroglobulin levels on these measures of change.

Progression-free survival [ Time Frame: Time from start of treatment to time of progression or death, whichever occurs first, assessed up to 1 year ]

Duration of objective response as assessed by the RECIST v1.1 [ Time Frame: From date of documentation of response to the date of progression or death, assessed up to 1 year ]

Evaluated using the methods of Kaplan and Meier.

Progression-free survival [ Time Frame: Time from start of treatment to time of progression or death, whichever occurs first, assessed up to 1 year ]

The Kaplan-Meier method will be used.

Overall survival [ Time Frame: Time from start of treatment to time of death, assessed up to 1 year ]

The Kaplan-Meier method will be used.

Incidence of severe (grade 3+) adverse events, graded according to the National Cancer Institute (NCI) CTCAE v4.0 [ Time Frame: Up to 1 year ]

The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns. Tolerability of the regimens will be assessed through assessing the number of patients who required dose modifications and/or dose delays. . In addition, the proportion of patients who go off treatment due to adverse reactions or even those who refuse further treatment for lesser toxicities that inhibit their willingness to continue participation on the trial will be captured.

Side-by-side boxplots will be used to assess possible differences in this change between responders and non-responders, and scatterplots can assess the influence of baseline thyroglobulin levels on these measures of change.

This phase II trial studies how well cabozantinib-s-malate works in treating patients with thyroid cancer that does not respond to treatment. Cabozantinib-s-malate may stop the growth of thyroid cancer by blocking some of the enzymes needed for cell growth. Cabozantinib-s-malate may also stop the growth of thyroid cancer by blocking blood flow to the tumor.

Detailed Description

PRIMARY OBJECTIVES:

I. The objective response rate, defined as the proportion of patients who have had a partial response (PR) or complete response (CR) within the first 6 months after initiation of therapy with cabozantinib (cabozantinib-s-malate).

Patients receive cabozantinib-s-malate PO daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Interventions:

Drug: Cabozantinib S-malate

Other: Laboratory Biomarker Analysis

Publications *

Not Provided

* Includes publications given by the data provider as well as publications
identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.

Recruitment Information

Recruitment Status ICMJE

Suspended

Estimated Enrollment ICMJE

25

Completion Date

Not Provided

Estimated Primary Completion Date

June 1, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria ICMJE

Inclusion Criteria:

Patients must have histologically or cytologically confirmed papillary thyroid cancer, follicular thyroid cancer or hurthle cell thyroid cancer (cancer, follicular variant of papillary thyroid cancers or any of the above mixed histology will be allowed; these patients will be enrolled on Arm A of the trial); patients with the following aggressive histologies will be enrolled on Arm B of the trial; tall cell, insular or poorly differentiated thyroid cancer

Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 2.0 cm with conventional techniques or as >= 1.0 cm (or >= 1.5 cm in short axis for lymph node) with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam

Patients must have radioactive iodine (RAI)-refractory/resistant disease as defined by one or more of the following criteria:

One or more measurable lesions that do not demonstrate RAI uptake

One or more measurable lesions progressive by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 within 12 months of prior RAI therapy

One or more measurable lesion present after cumulative RAI dose of >= 600 mCi

Patients must have "progressed on" up to 2 lines of prior vascular endothelial growth factor receptor (VEGFR)-targeted therapy (including but not limited to sorafenib, sunitinib, vandetanib, pazopanib, or lenvatinib) as defined by progressive disease per RECIST while receiving VEGFR-targeted therapy; Note: patients who progressed on kinase inhibitor that target VEGFR and MET will not be eligible

Prior external beam radiation, systemic cytotoxic chemotherapy or BRAF- or non-VEGFR-targeted therapies will be allowed, provided that >= 4 weeks has elapsed since receiving prior treatment and they have recovered to =< grade 1 treatment-related toxicities

Lipase < 2.0 x ULN and no radiologic or clinical evidence of pancreatitis

Urine protein/creatinine ratio (UPCR) =< 1

Serum phosphorus, calcium, magnesium and potassium >= LLN

Prothrombin time (PT) < 1.3 x ULN

International normalized ratio (INR) < 1.3 x ULN

Partial thromboplastin time (PTT) test < 1.3 x ULN

Women of childbearing potential must have a negative pregnancy test at screening; women of childbearing potential include women who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are not postmenopausal; postmenopause is defined as amenorrhea >= 12 consecutive months; Note: women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, ovarian suppression or any other reversible reason

Women of child-bearing potential and men must agree to use adequate contraception; women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of cabozantinib administration; sexually active subjects (men and women) must agree to use medically accepted barrier methods of contraception (e.g., male or female condom) during the course of the study and for 4 months after the last dose of study drug(s), even if oral contraceptives are also used; all subjects of reproductive potential must agree to use both a barrier method and a second method of birth control during the course of the study and for 4 months after the last dose of study drug(s)

Ability to understand and the willingness to sign a written informed consent document

The subject has received radionuclide treatment =< 6 weeks of the first dose of study treatment

The subject has received any other type of investigational agent =< 28 days before the first dose of study treatment

The subject has not recovered to baseline or Common Terminology Criteria for Adverse Events (CTCAE) =< grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant adverse events (AEs)

The subject has active brain metastases or epidural disease; subjects with brain metastases previously treated with whole brain radiation or radiosurgery or subjects with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least 2 weeks before starting study treatment are eligible; baseline brain imaging with contrast-enhanced CT or MRI scans for subjects with known brain metastases is required to confirm eligibility; eligible patients with brain metastases can be taking anti-convulsant medications but only non-enzyme inducing anti-epileptic agents (NEIAED) will be allowed

The subject requires chronic concomitant treatment of strong cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, and St. John's Wort) or strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, voriconazole, and posaconazole); Note: because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated lists; medical reference texts such as the Physicians' Desk Reference may also provide this information; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product

The subject has experienced any of the following:

Clinically-significant gastrointestinal bleeding =< 6 months before the first dose of study treatment

Hemoptysis of >= 0.5 teaspoon (2.5 mL) of red blood =< 3 months before the first dose of study treatment

Any other signs indicative of pulmonary hemorrhage =< 3 months before the first dose of study treatment

The subject has radiographic evidence of cavitating pulmonary lesion(s)

The subject has tumor that is invading or encasing any major blood vessels

The subject has evidence of tumor invading the gastrointestinal (GI) tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor =< 28 days before the first dose of cabozantinib

The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:

Cardiovascular disorders including:

Congestive heart failure (CHF): New York Heart Association (NYHA) class III (moderate) or class IV (severe) at the time of screening

Any of the following =< 6 months before the first dose of study treatment:

Abdominal fistula

Gastrointestinal perforation

Bowel obstruction or gastric outlet obstruction

Intra-abdominal abscess; Note: complete resolution of an intra-abdominal abscess must be confirmed prior to initiating treatment with cabozantinib even if the abscess occurred more than 6 months before the first dose of study treatment

Other disorders associated with a high risk of fistula formation including percutaneous endoscopic gastrostomy (PEG) tube placement =< 3 months before the first dose of study therapy

Other clinically significant disorders such as:

Active infection requiring systemic treatment =< 28 days before the first dose of study treatment

Serious non-healing wound/ulcer/bone fracture =< 28 days before the first dose of study treatment

History of organ transplant

History of major surgery as follows:

Major surgery =< 3 months of the first dose of cabozantinib if there were no wound healing complications or =< 6 months of the first dose of cabozantinib if there were wound complications

Minor surgery =< 1 months of the first dose of cabozantinib if there were no wound healing complications or =< 3 months of the first dose of cabozantinib if there were wound complications

In addition, complete wound healing from prior surgery must be confirmed at least 28 days before the first dose of cabozantinib irrespective of the time from surgery

The subject is unable to swallow tablets

The subject has a corrected QT interval calculated by the Fridericia or Bazett's formula (QTcF) > 480 ms within 28 days before registration; Note: if initial QTcF or QTcB is found to be > 480 ms, two additional electrocardiograms (EKGs) separated by at least 3 minutes should be performed; if the average of these three consecutive results for QTcF or QTcB is =< 480 ms, the subject meets eligibility in this regard

The subject is unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee

The subject has had evidence within 2 years of the start of study treatment of another malignancy which required systemic treatment

History of allergic reactions attributed to compounds of similar chemical or biologic composition to cabozantinib

Any of the following:

Pregnant women

Nursing women

Men or women of childbearing potential who are unwilling to employ adequate contraception

Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy; Note: patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial

The subject has received prior treatment with a small molecule kinase inhibitor or a hormonal therapy (including investigation kinase inhibitors or hormones) within 14 days or five half-lives of the compound or active metabolites, whichever is longer, before the first dose of the treatment

Sex/Gender

Sexes Eligible for Study:

All

Ages

18 Years and older (Adult, Senior)

Accepts Healthy Volunteers

No

Contacts ICMJE

Contact information is only displayed when the study is recruiting subjects